Substituted bicyclic and tricyclic thrombin receptor antagonists

ABSTRACT

Substituted bicyclic and tricyclic modified himbacine derivative of the formula: 
                         
or a pharmaceutically acceptable salt or solvate of said compound wherein  represents an optional double bond and wherein E n , F n , G n , Z n , J n , X, R 3 , R 9 , R 10 , R 11 , R 32 , R 33 , B and Het are herein defined are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other agents is also claimed.

RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 60/817,302, filed Jun. 29, 2006, herein incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to himbacine derivatives, which can beuseful as thrombin receptor antagonists in the treatment of diseasesassociated with thrombosis, atherosclerosis, restenosis, hypertension,angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke,neurodegenerative diseases and cancer. Thrombin receptor antagonists arealso known as protease activated receptor-1 (PAR-1) antagonists. Thecompounds of the invention also can be useful as cannabinoid (CB₂)receptor inhibitors for the treatment of rheumatoid arthritis, systemiclupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renalischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatorydisorders of the lungs and gastrointestinal tract, and respiratory tractdisorders such as reversible airway obstruction, chronic asthma andbronchitis. The invention also relates to pharmaceutical compositionscomprising said compounds.

Thrombin is known to have a variety of activities in different celltypes. Thrombin receptors are known to be present in such cell types ashuman platelets, vascular smooth muscle cells, endothelial cells andfibroblasts. It is therefore expected that thrombin receptor antagonistswill be useful in the treatment of thrombotic, inflammatory,atherosclerotic and fibroproliferative disorders, as well as otherdisorders in which thrombin and its receptor play a pathological role.

Thrombin receptor antagonist peptides have been identified based onstructure-activity studies involving substitutions of amino acids onthrombin receptors. In Bernatowicz et al., J. Med. Chem., 39 (1996), p.4879-4887, tetra- and pentapeptides are disclosed as being potentthrombin receptor antagonists, for exampleN-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH₂ andN-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH₂. Peptidethrombin receptor antagonists are also disclosed in WO 94/03479,published Feb. 17, 1994.

Cannabinoid receptors belong to the superfamily of G-protein coupledreceptors. They are classified into the predominantly neuronal CB₁receptors and the predominantly peripheral CB₂ receptors. Thesereceptors exert their biological actions by modulating adenylate cyclaseand Ca⁺² and K⁺ currents. While the effects of CB₁ receptors areprincipally associated with the central nervous system, CB₂ receptorsare believed to have peripheral effects related to bronchialconstriction, immunomodulation and inflammation. As such, a selectiveCB₂ receptor binding agent is expected to have therapeutic utility inthe control of diseases associated with rheumatoid arthritis, systemiclupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renalischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatorydisorders of the lungs and gastrointestinal tract, and respiratory tractdisorders such as reversible airway obstruction, chronic asthma andbronchitis (R. G. Pertwee. Curr. Med. Chem. 6(8), (1999), 635; M.Bensaid, Molecular Pharmacology, 63 (4), (2003), 908.).

Himbacine, a piperidine alkaloid of the formula

has been identified as a muscarinic receptor antagonist. The totalsynthesis of (+)-himbacine is disclosed in Chackalamannil et al., J. Am.Chem. Soc., 118 (1996), p. 9812-9813. Properties of himbacine derivedcompounds that are thrombin receptor antagonists have been described.(Chackalamannil et. al. J. Med. Chem., 48 (2005), 5884-5887.)

Substituted tricyclic thrombin receptor antagonists are disclosed inU.S. Pat. Nos. 6,063,847, 6,326,380 and U.S. Ser. Nos. 09/880,222 (WO01/96330), 10/271,715, and 10/412,982.

SUMMARY OF THE INVENTION

The present invention relates to compounds represented by the formula I:

or a pharmaceutically acceptable salt, solvate, or ester of saidcompound, wherein

represents a double bond or a single bond, as permitted by the valencyrequirement; with the proviso that R¹⁰ or R¹¹ are absent when the carbonto which R¹⁰ or R¹¹ are attached is part of a double bond;

B is —(CH₂)_(n3)—, —(CH₂)—O—, —(CH₂)S—, —(CH₂)—NR⁶—, —C(O)NR⁶—.—NR⁶C(O)—,

—(CH₂)_(n4)CR¹²═CR^(12a)(CH₂)_(n5)— or —(CH₂)_(n4)C≡C(CH₂)_(n5)—,wherein n₃ is 0-5, n₄ and n₅ are independently 0-2, and R¹² and R^(12a)are independently selected from the group consisting of hydrogen, alkyland halogen;

E, F, G, Z, and J are independently selected from the group consistingof —NR(R¹)—, NR²,

—(CR¹R²)—, —O—,

—S—, —S(O)—, —S(O)₂— and

with the provisos that selection of E, F, G, Z, and J does not result inadjacent oxygen or sulfur atoms and that at least one carbon atom appearbetween said oxygen, nitrogen or sulfur atoms;

each n is 0, 1 or 2 with the proviso that all n variables cannot be 0;

Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atomscomprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S, with the proviso thatthere are no adjacent oxygen or sulfur atoms present in theheteroaromatic group, wherein a ring nitrogen can form an N-oxide or aquaternary group with an alkyl group, wherein Het is attached to B by acarbon atom ring member, and wherein the Het group is substituted by 1to 4 moieties, W, wherein each W is independently selected from thegroup consisting of

-   hydrogen,-   alkyl,-   fluoroalkyl, difluoroalkyl, trifluoroalkyl, haloalkyl, dihaloalkyl,    trihaloalkyl,-   cycloalkyl, cycloalkyl substituted by alkyl, alkenyl, or alkynyl,-   heterocycloalkyl, heterocycloalkyl substituted by alkyl, alkenyl, or    alkynyl,-   R²¹-arylalkyl, R²¹-aryl-alkenyl,-   heteroaryl, heteroarylalkyl, heteroarylalkenyl,-   hydroxyalkyl, dihydroxyalkyl,-   aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl,-   thioalkyl,-   alkoxy, alkenyloxy,-   halogen,-   —NR⁴R⁵,-   —SH,-   —CN,-   —OH,-   —C(O)OR¹⁷, —COR¹⁶, —OS(O₂)CF₃, —CH₂OCH₂CF₃,-   alkylthio,-   —C(O)NR⁴R⁵,-   —OCHR⁶-phenyl,-   phenoxyalkyl,-   —NHCOR¹⁶,-   —NHSO₂R¹⁶,-   biphenyl,-   —OC(R⁶)₂COOR⁷, —OC(R⁶)₂C(O)NR⁴R⁵,-   alkoxy substituted by alkyl, amino or —NHC(O)OR¹⁷,-   aryl,-   aryl substituted by 1 to 3 substituents independently selected from    the group consisting of alkyl, halogen, alkoxy, methylenedioxy,    carboxylic acid, carboxamide, amine, urea, amide, sulfonamide, —CN,    —CF₃, —OCF₃, —OH, alkylamino-, di-(alkyl)amino-, —NR²⁵R²⁶alkyl-,    hydroxyalkyl-, —C(O)OR¹⁷, —COR¹⁷, —NHCOR¹⁶, —NHS(O)₂R¹⁶,    —NHS(O)₂CH₂CF₃, —C(O)NR²⁵R²⁶, NR²⁵R²⁶, —S(O)R¹³, —S(O)₂R¹³ and-   —SR¹³,-   or alkyl optionally substituted with —NR¹R², —NR¹COR², —NR¹CONR¹R²,-   —NR¹C(O)OR², —NR¹S(O)₂R², —NR¹S(O)₂NR¹R², —C(O)OH, —C(O)OR¹,    —CONR¹R²heteroaryl, hydroxyalkyl, alkyl, —S(O)₂-alkyl, —C(O)NR⁴R⁵ or    heteroaryl; wherein adjacent carbons on the Het ring can optionally    form a ring with a methylenedioxy group;

R¹ and R² are independently selected from the group consisting ofhydrogen, halogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl,cycloalkyl, alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, amine,aminoalkyl, aryl, thiohydroxy, CN, and thioalkyl; or

R¹ and R² when attached to nitrogen, taken together, form a mono orbicyclic heterocyclic ring of 4 to 10 atoms, with 1-3 heteroatomsselected from —O—, —N—, —S—,

—S(O)—, —S(O)₂— and

with the proviso that S and O ring atoms are not adjacent to each other,where said heterocyclic ring is unsubstituted or substituted with one ormore groups independently selected from alkyl, halogen, hydroxy, alkoxy,aryloxy and arylalkoxy;

R³ is R¹, fluoroalkoxy, difluoroalkoxy, trifluoroalkoxy, cycloalkyloxy,alkenyloxy, alkoxy, arylalkoxy, arylalkenyloxy, heteroarylalkoxy,heteroarylalkenyloxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aryloxyor thioalkoxy,

R⁶ is hydrogen, alkyl or phenyl;

R⁷ is hydrogen or alkyl;

each R¹³ is independently selected from hydrogen, alkyl, cycloalkyl,haloalkyl, halogen, —(CH₂)_(n6)NHC(O)OR^(16b), —(CH₂)_(n6)NHC(O)R^(16b),—(CH₂)_(n6)NHC(O)NR⁴R⁵, —(CH₂)_(n6)NHSO₂R¹⁶, —(CH₂)_(n6)NHSO₂NR⁴R⁵, and—(CH₂)_(n6)C(O)NR²⁸R²⁹, where n₆ is 0-4;

each R¹⁴ is independently selected from the group consisting ofhydrogen, alkyl, —OH, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, halogen, haloalkyl,—(CH₂)_(n6)NHC(O)OR^(16b), —(CH₂)_(n6)NHC(O)R^(16b),—(CH₂)_(n6)NHC(O)NR⁴R⁵, —(CH₂)_(n6)NHSO₂R¹⁶, —(CH₂)_(n6)NHSO₂NR⁴R⁵, and—(CH₂)_(n6)C(O)NR²⁸R²⁹ where n₆ is 0-4; where R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, alkyl,phenyl, benzyl and cycloalkyl, or R⁴ and R⁵ together can form a ringwith the nitrogen to which they are attached, wherein said ring formedby R⁴ and R⁵ is optionally substituted with ═O, OH, OR¹ or —C(O)OH; or

R¹³ and R⁴ taken together form a spirocyclic or a heterospirocyclic ringof 3-6 ring atoms, wherein said heterospirocyclic ring contains 2 to 5carbon ring atoms and 1 or 2 hetero ring atoms selected from the groupconsisting of O, S and N;

R¹⁶ is independently selected from the group consisting of hydrogen,alkyl, phenyl and benzyl;

R^(16a) is independently selected from the group consisting of hydrogen,alkyl, phenyl and benzyl;

R^(16b) is hydrogen, alkoxy, alkyl, alkoxyalkyl-, R²²—O—C(O)-alkyl-,cycloalkyl, R²¹-aryl, R²¹-arylalkyl, haloalkyl, alkenyl, halosubstituted alkenyl, alkynyl, halo substituted alkynyl, R²¹-heteroaryl,(R²¹-heteroaryl)-alkyl-, (R²¹-heterocycloalkyl)-alkyl-, R²⁸R²⁹N-alkyl-,R²⁸R²⁹N—C(O)-alkyl-, R²⁸R²⁹N—C(O)O-alkyl-, R²⁸OC(O)N(R²⁹)-alkyl-,R²⁸S(O)₂N(R²⁹)-alkyl-, R²⁸R²⁹N—C(O)—N(R²⁹)-alkyl-,R²⁸R²⁹N—S(O)₂N(R²⁹)-alkyl-, R²⁸—C(O)N(R²⁹)-alkyl-, R²⁸R²⁹N—S(O)₂-alkyl-,HOS(O)₂-alkyl-, (OH)₂P(O)₂-alkyl-, R²⁸—S—alkyl-, R²⁸—S(O)₂-alkyl- orhydroxyalkyl;

R¹⁷ is independently selected from the group consisting of hydrogen,alkyl, phenyl and benzyl;

R¹⁸ and R¹⁹ are hydrogen, alkyl, aryl, R²¹-aryl, heteroaryl, cycloalkyl,heterocyclyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl,arylalkoxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl,cycloalkyloxyalkyl, (heterocyclyl)alkyloxyalkyl, alkoxyalkyloxyalkyl,—S(O)₂-alkyl, —C(NH)NR¹R² or alkyl substituted with one or two moietiesselected from cycloalkyl, halogen, hydroxy, —NR¹R², —NR¹C(O)R²,—NR¹C(O)NR¹R², —NR¹C(O)OR², —NR¹S(O)₂R², —NR¹S(O)₂NR¹R², —C(O)OH,—C(O)OR¹ and —C(O)NR¹R²; or

R¹⁸ and R¹⁹ together with the nitrogen to which they are attached, forma mono or bicyclic heterocyclic ring of 4 to 10 atoms, having 1-3 heteroring atoms selected from —O—, —N—, —S—, —S(O)—, —S(O)₂ and —C(O)—, withthe proviso that S and O atoms are not adjacent to each other, the ringbeing unsubstituted or substituted with one or more groups selected fromalkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —NR¹R², —NR¹COR²,—NR¹C(O)NR¹R², —NR¹C(O)OR², —NR¹S(O)₂R², —NR¹S(O₂)NR¹R², —C(O)OR¹,—CONR¹R² and alkyl substituted with —NR¹R², —NR¹COR², —NR¹CONR¹R²,—NR¹C(O)OR², —NR¹S(O)₂R², —NR¹S(O)₂NR¹R², —C(O)OR¹ or —CONR¹R²,

R²¹ is 1 to 3 moieties and each R²¹ is independently selected from thegroup consisting of hydrogen, —CN, —CF₃, —OCF₃, halogen, —NO₂, alkyl,—OH, alkoxy, alkylamino-, di-(alkyl)amino-, —NR²⁵R²⁶alkyl-,hydroxyalkyl-, —C(O)OR¹⁷, —COR¹⁷, —NHCOR¹⁶, —NHS(O)₂R¹⁶, —C(NH)—NH₂,—NHS(O)₂CH₂CF₃, —C(O)NR²⁵R²⁶, —NR²⁵—C(O)—NR²⁵R²⁶, —S(O)R¹⁶, —S(O)₂R¹⁶,—SR¹⁶; —SO₂NR⁴R⁵ and —CONR⁴, R⁵; or two adjacent R²¹ moieties can form amethylenedioxy group;

R²² is hydrogen, alkyl, phenyl, benzyl, —COR¹⁶; —CONR¹⁸R¹⁹,—COR²³—S(O)R³¹, —S(O)₂R³¹, —S(O₂)NR²⁴R²⁵ or —C(O)OR²⁷;

wherein R³⁵ and R³⁶ are independently selected from the group consistingof hydrogen, alkyl, and R³⁷-substituted alkyl, wherein R³⁷ is selectedfrom the group consisting of HO—, HS—, CH₂S—, —NH₂, phenyl,p-hydroxyphenyl and indolyl; or R²³ is alkyl; haloalkyl; alkenyl;haloalkenyl; alkynyl; cycloalkyl; cycloalkylalkyl; cycloalkylsubstituted by 1 to 3 substituents selected from the group consisting ofalkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy,—NR¹R², —NR¹C(O)R²—NR¹C(O)NR¹R²—NR¹C(O)OR²—NR¹S(O)₂R²—NR¹S(O)₂NR¹R²,—C(O)OR¹ and —CONR¹, R²; aryl; aralkyl; heteroaryl; heterocycloalkyl;alkyl substituted with —NR¹R², —NR¹COR², —NR¹CONR¹R², —NR¹C(O)OR²,—NR¹S(O₂)R², —NR¹S(O₂)NR¹R², —C(O)OR¹, —CONR¹R² and —SO₃H;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl,halocycloalkyl, alkoxyalkyl, hydroxy and alkoxy;

R²⁷ is 1 to 3 moieties and each R²⁷ is selected from the groupconsisting of hydrogen, alkyl, and cycloalkyl, wherein R²⁷ is optionallysubstituted with —OH, —C(O)OH, halogen and alkoxy;

R²⁸ and R²⁹ are independently selected from the group consisting ofhydrogen, alkyl, alkoxy; arylalkyl, heteroaryl, heteroarylalkyl,hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, andhaloalkyl; or

R²⁸ and R²⁹ taken together form a spirocyclic or a heterospirocyclicring having 3-6 ring atoms;

R³² and R³³ are independently selected from the group consisting ofhydrogen, R³⁴-alkyl, R³⁴-alkenyl, R³⁴-alkynyl, R⁴⁰-heterocycloalkyl,R³⁸-aryl, R³⁸-aralkyl, R⁴²-cycloalkyl, R⁴²-cycloalkenyl, —OH,—OC(O)R⁴³—C(O)OR⁴³, —C(O)R⁴³—O(NR⁴³R⁴⁴, —NR⁴³R⁴⁴, —NR⁴³C(O)R⁴⁴,—NR⁴³C(O)R⁴⁴, —NR⁴³C(O)NR⁴R⁴R⁴—NHS(O)₂R⁴³, —OC(O)NR⁴³R⁴⁴, R³⁷-alkoxy,R³⁷-alkynyloxy, R³⁷-alkynyloxy, R⁴⁰-heterocycloalkyloxy,R⁴²-cycloalkyloxy, R⁴²-cyclo-alkenyloxy, R⁴²-cycloalkyl-NH—, —NHSO₂NHR¹⁶and —CH(═NOR¹⁷);

or R³² and R³³ are combined to form a ring structure Q, below

where

R⁹ is hydrogen, OH, alkoxy, halogen or haloalkyl;

Q is fused R-substituted aryl, R-substituted heteroaryl, R-substitutedheterocyclic ring of 4-8 atoms containing 1-3 heteroatoms selected fromO, S, S(O), S(O)₂ and NR²² with the proviso that S and O cannot beadjacent to one another; or

Q is

wherein R¹⁰ and R¹¹ are independently selected from the group consistingof R¹ and —OR¹, provided that when ring Q is aromatic and the carbonatoms bearing R¹⁰ and R¹¹ are connected by a double bond, R¹⁰ and R¹¹are absent;

R is 1 to 5 moieties and each R is independently selected from the groupconsisting of hydrogen, alkyl, halogen, hydroxy, amino, alkylamino,dialkylamino, alkoxy, —COR¹⁶, —C(O)R¹⁷, —C(O)NR⁴R⁵, —SOR¹⁶, —S(O₂)R¹⁶,—NR¹⁶COR^(16a), —NR¹⁶C(O)OR^(16a), —NR¹⁶CONR⁴R⁵, —NR¹⁶S(O₂)NR⁴R⁵,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl,hydroxyalkyl, aminoalkyl, aryl and thioalkyl;

R³⁴ is 1 to 3 moieties and each R³⁴ is independently selected from thegroup consisting of hydrogen, halogen, —OH, alkoxy, R⁴⁷-aryl,alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)—, heterocycloalkyl,R³⁹-cycloalkyl, R³⁹-cycloalkenyl, —OC(O)R⁴³, —C(O)OR⁴³, —C(O)R⁴³,—C(O)NR⁴³R⁴⁴, —NR⁴³R⁴⁴, —NR⁴³C(O)R⁴⁴, —NR⁴³C(O)NR⁴⁴R⁴⁵, —NHSO₂R⁴³,—OC(O)NR⁴³R⁴⁴, R³⁴-alkenyloxy, R³⁴-alkynyloxy, R⁴⁰-heterocycloalkyloxy,R⁴²-cycloalkyloxy, R⁴²-cycloalkenyloxy, R⁴²-cycloalkyl-NH—, —NHSO₂NHR¹⁶and —CH(═NOR¹⁷);

R³⁸ is 1 to 3 moieties and each R³⁸ is independently selected from thegroup consisting of hydrogen, heterocycloalkyl, halogen, —C(O)OR⁴⁸1-CN,—C(O)NR⁴⁹R⁵⁰, —NR⁵¹C(O)R⁵², —OR⁴⁸, cycloalkyl, cycloalkylalkyl,alkylcycloalkylalkyl, haloalkylcycloalkylalkyl, hydroxyalkyl,alkoxyalkyl, and R⁵²-heteroaryl; or two R³⁸ groups on adjacent ringcarbons form a fused methylenedioxy group;

R³⁹ is 1 to 3 moieties and each R³⁹ is independently selected from thegroup consisting of hydrogen, halogen and alkoxy;

R⁴⁰ is 1 to 3 moieties and each R⁴⁰ is independently selected from thegroup consisting of hydrogen, R⁴¹-alkyl, R⁴¹-alkenyl and R⁴¹-alkynyl;

R⁴¹ is hydrogen, —OH or alkoxy;

R⁴² is 1 to 3 moieties and each R⁴² is independently selected from thegroup consisting of hydrogen, alkyl, —OH, alkoxy and halogen;

R⁴³, R⁴⁴ and R⁴⁵ are independently selected from the group consisting ofhydrogen, alkyl, alkoxyalkyl, R³⁸-arylalkyl, R⁴⁶-cycloalkyl,R⁵³-cycloalkylalkyl, R³⁸-aryl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl and heteroarylalkyl;

R⁴⁶ is hydrogen, alkyl, hydroxyalkyl or alkoxy;

R⁴⁷ is 1 to 3 moieties and each R⁴⁷ is independently selected from thegroup consisting of hydrogen, alkyl, —OH, halogen, —CN, alkoxy,trihaloalkoxy, alkylamino, di(alkyl)amino, —OCF₃, hydroxyalkyl, —CHO,—C(O)alkylamino, —C(O)di(alkyl)amino, —NH₂, —NHC(O)alkyl and—N(alkyl)C(O)alkyl;

R⁴⁸ is hydrogen, alkyl, haloalkyl, dihaloalkyl or trifluoroalkyl;

R⁴⁹ and R⁵⁰ are independently selected from the group consisting ofhydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R⁴⁹ and R⁵⁰ togetherare —(CH₂)₄—, —(CH₂)₅— or —(CH₂)₂—NR³⁹—(CH₂)₂— and form a ring with thenitrogen to which they are attached;

R⁵¹ and R⁵² are independently selected from the group consisting ofhydrogen, alkyl, aralkyl, phenyl and cycloalkyl, or R⁵¹ and R⁵² in thegroup —NR³⁹C(O)R⁴⁰, together with the nitrogen atoms to which they areattached, form a cyclic lactam having 5-8 ring members;

R⁵³ is hydrogen, alkoxy, —SOR¹⁶, —SO₂R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁸R¹⁹,alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, aralkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl,hydroxyalkyl, aminoalkyl, aryl, thioalkyl, alkoxyalkyl oralkylaminoalkyl; and

R⁵⁴ is selected from the group consisting of hydrogen; alkyl;fluoroalkyl; difluoroalkyl; trifluoroalkyl; cycloalkyl; cycloalkylsubstituted by 1 to 3 substituents selected from the group consisting ofalkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy,—NR¹R², —NR¹C(O)R², —NR¹C(O)NR¹R², —NR¹C(O)OR², —NR¹S(O)₂R²,—NR¹S(O)₂NR¹, R²—C(O)OH, —C(O)OR¹ and —CONR¹R²; alkenyl; alkoxy;arylalkyl; arylalkenyl; heteroarylalkyl; heteroarylalkenyl; hydroxy;alkoxy; hydroxyalkyl; alkoxyalkyl; aminoalkyl; aryl; heteroaryl;thioalkyl and alkyl substituted by 1 to 3 subsituents selected from thegroup consisting of urea, sulfonamide, carboxamide, carboxylic acid,carboxylic ester and sulfonyl urea.

Pharmaceutical compositions comprising at least one compound of formulaI and at least one pharmaceutically acceptable carrier are alsoprovided.

The compounds of the present invention can be useful as Thrombinreceptor antagonists, also known as PAR-1 antagonists, or as cannabinoid(CB₂) receptor antagonists. Thrombin receptor antagonist compounds ofthe present invention can have anti-thrombotic, anti-plateletaggregation, anti-atherosclerotic, anti-restenotic anti-coagulant,and/or anti-inflammatory activity. CB₂ receptor inhibitor compounds ofthe present invention can be useful for the treatment of rheumatoidarthritis, systemic lupus erythematosus, multiple sclerosis, diabetes,osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia,nephritis, inflammatory disorders of the lungs and gastrointestinaltract, and respiratory tract disorders such as reversible airwayobstruction, chronic asthma and bronchitis.

Compounds of the invention can be useful for the treatment ofthrombosis, atherosclerosis, restenosis, hypertension, angina pectoris,angiogenesis related disorders, arrhythmia, a cardiovascular orcirculatory disease or condition, heart failure, acute coronary syndrome(ACS), myocardial infarction, glomerulonephritis, thrombotic stroke,thromboembolytic stroke, peripheral vascular diseases, deep veinthrombosis, venous thromboembolism, a cardiovascular disease associatedwith hormone replacement therapy, disseminated intravascular coagulationsyndrome, cerebral infarction, as well as other disorders in whichthrombin and its receptor play a pathological role.

In particular, compounds of the present invention are used to treatacute coronary syndrome, myocardial infarction or thrombotic stroke.

Compounds of the present invention can also be used in a method to treator prevent a condition associated with cardiopulmonary bypass surgery(CPB) comprising administering an effective amount of at least onethrombin receptor antagonist to a subject of said surgery. CPB surgeryincludes coronary artery bypass surgery (CABG), cardiac valvular repairand replacement surgery, pericardial and aortic repair surgeries. Inparticular, the present invention relates to a method of treating orpreventing a condition associated with CABG surgery comprisingadministering an effective amount of at least one thrombin receptorantagonist to a subject of said surgery. The conditions associated withCABG are selected from the group consisting of: bleeding; thromboticvascular events such as thrombosis, restenosis; vein graft failure;artery graft failure; atherosclerosis, angina pectoris; myocardialischemia; acute coronary syndrome myocardial infarction; heart failure;arrhythmia; hypertension; transient ischemic attack; cerebral functionimpairment; thromboembolic stroke; cerebral ischemia; cerebralinfarction; thrombophlebitis; deep vein thrombosis; and, peripheralvascular disease.

Certain embodiments of this invention also relate to a method of usingan effective amount of at least one compound of Formula I in combinationwith one or more additional agents for the treatment of thrombosis,atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesisrelated disorders, arrhythmia, a cardiovascular or circulatory diseaseor condition, heart failure, acute coronary syndrome (ACS), myocardialinfarction, glomerulonephritis, thrombotic stroke, thromboembolyticstroke, peripheral vascular diseases, deep vein thrombosis, venousthromboembolism, a cardiovascular disease associated with hormonereplacement therapy, disseminated intravascular coagulation syndrome,cerebral infarction, It is contemplated that a combination of thisinvention may be useful in treating more than one of the diseaseslisted.

Pharmaceutical compositions comprising a therapeutically effectiveamount of a combination of at least one compound of formula I and atleast one additional cardiovascular agent in a pharmaceuticallyacceptable carrier are also provided.

It is further contemplated that the combination of the invention can beprovided as a kit comprising in a single package at least one compoundof formula I in a pharmaceutical composition, and at least one separatepharmaceutical composition comprising a cardiovascular agent.

DETAILED DESCRIPTION

In one embodiment, the present invention provides compounds representedby structural formula I, or pharmaceutically acceptable salt thereof,wherein the various moieties are as described as above.

For compounds of Formula I, preferred embodiments of the compounds offormula I are as follows;

Additional preferred embodiments of the compounds of formula I are asfollows:

In another embodiment, in Formula I, R³² and R³³ are combined to formthe ring structure Q.

In another embodiment, in formula I,

In another embodiment, in formula I,

In another embodiment, in formula I, R³² and R³³, which can be the sameor different, are each alkyl.

In another embodiment, in formula I, R³² and R³³, which can be the sameor different, are each methyl.

In another embodiment, in formula I,

In another embodiment, in formula I Het is unsubstituted pyridyl.

In another embodiment, in formula I Het is pyridyl substituted with W,wherein said W is aryl substituted with at least one —CN or at least onehalogen.

In another embodiment, in formula I Het is pyridyl substituted with W,wherein said W is phenyl, which can be unsubstituted or substituted withat least one moiety, which can be the same or different, wherein saidmoiety is independently selected from the group consisting —CN orhalogen.

In another embodiment, in formula I E_(n) is N(R¹)—, —CO₂—,

—O—, or

wherein n is 1.

In another embodiment, in formula I F_(n) is N(R¹)—,

wherein n is 1.

In another embodiment, in formula I, G_(n) is

wherein R⁶ and R¹ are each hydrogen, alkyl or phenyl, and furtherwherein n is 1.

In another embodiment, in formula I, G_(n) is G₀.

In another embodiment, in formula I Z_(n) is

wherein n is 1.

In another embodiment, in formula I Z_(n) is CH₂—, wherein n is 1.

In another embodiment, in formula I J_(n) is —CH₂—, wherein n is 1.

In another embodiment, in formula I X is

In another embodiment, in formula I R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³² and R³³ are each methyl;

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

F_(n) is —O—, wherein n is 1;

E_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

F_(n) is —O—, wherein n is 1;

E_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

E_(n) is —O—, wherein n is 1;

G_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

E_(n) is —O—, wherein n is 1;

G_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

G_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—;

Z_(n) is —CH₂—;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1

G_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—;

Z_(n) is —CH₂—,

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —CH₂, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—;

Z_(n) is —CH₂—;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula.

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1

E_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—;

Z_(n) is —CH₂—;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl; cycloalkyl; alkenyl, alkoxy,arylalkyl; arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —CH₂—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

H_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂, wherein n is 1-;

Z_(n) is —CH₂—, wherein n is 1;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

Z_(n) is —CH₂—, wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula.

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1

wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³² and R³³ are each methyl

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R¹ is selected from the group consisting of hydrogen, alkyl,fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, alkoxy,arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxy,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl and thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1;

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl; and

R³² and R³³ are each methyl,

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl,

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl; and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl; and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof wherein

Q is

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1;

wherein n is 1;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl;

R⁶ is hydrogen, alkyl, or phenyl and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

wherein n is 1;

wherein n is 1

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl;

R⁶ is hydrogen, alkyl, or phenyl and

R³² and R³³ are each methyl.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl, and

R³, R⁹, R¹⁰ and R¹¹ are H.

In another embodiment, this invention discloses a compound of theFormula:

or a pharmaceutically acceptable salt, solvate, ester, or prodrugthereof, wherein

Het is W-substituted pyridyl;

W is phenyl substituted by at least one halogen or at least one cyano;

wherein n is 1;

E_(n) is —O—, wherein n is 1;

G_(n) is G₀;

J_(n) is —CH₂—, wherein n is 1;

wherein n is 1;

R³, R⁹, R¹⁰ and R¹¹ are H;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl,alkenyl, alkoxy, arylalkyl, arylalkenyl, heteroarylalkyl,heteroarylalkenyl, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryland thioalkyl; and

R³² and R³³ are each methyl.

Non-limiting examples of compounds of Formula I include:

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Subject” includes both mammals and non-mammalian animals.

“Mammal”^(t) means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl,n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl, andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyd, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

The term “Het” is exemplified by the single ring, bicyclic andbenzofused heteroaryl groups as defined immediately above. Het groupsare joined to group B by a carbon ring member, e.g., Het is 2-pyridyl,3-pyridyl or 2-quinolyl. The Het ring can be substituted on anyavailable ring carbon by a group W; 1 to 4 W substituents can be presenton a Het ring.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkylene” refers to a corresponding bivalent ring, wherein thepoints of attachment to other groups include all positional isomers.

“Dihydroxyalkyl” refers to an alkyl chain substituted by two hydroxygroups on two different carbon atoms.

“Fluoroalkyl”, “difluoroalkyl” and “trifluoroalkyl” mean alkyl chainswherein the terminal carbon is substituted by 1, 2 or 3 fluoroatoms,respectively, e.g., —CF₃, —CH₂CF₃, —CH₂CHF₂ or —CH₂CH₂F.

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Preferred are fluoro, chloro or bromo, and more preferred are fluoro andchloro.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkys include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Preferred are fluoro, chloro or bromo, and more preferred are fluoro andchloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

The term “Boc” refers to N-tert-butoxycarbonyl.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” or “heterocycloalkyl” means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more “ring system substituents”which may be the same or different, and are as defined herein. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of suitable monocyclic heterocyclyl rings include piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone,and the like. “Heterocyclyl” may also mean a single moiety (e.g.,carbonyl) which simultaneously replaces two available hydrogens on thesame carbon atom on a ring system. Example of such moiety ispyrrolidone:

“Heterocyclylalkyl” or “heterocycloalkylalkyl” means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orSS-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem.

Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

-   -   there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

The term “heterospirocyclic” refers to a spirocyclic structurecontaining 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from thegroup consisting of N, S and O, provided that the heteroatoms are notadjacent.

“Alkylamino” means an alkyl-amino group in which the alkyl group is aspreviously described. The bond to the parent moiety is through theamino.

“Alkylaminoalkyl” means an alkyl-amino-alkyl group in which the alkylgroups are as previously described. The bond to the parent moiety isthrough the alkyl.

“Alkylcycloalkylalkyl” means an alkyl-cycloalkyl-alkyl group in whichthe alkyl and cycloalkyl groups are as previously described. The bond tothe parent moiety is through the alkyl.

“Alkylheteroaryl” means an alkyl-heteroaryl group in which the alkyl andheteroaryl groups are as previously described. The bond to the parentmoiety is through the heteroaryl.

“Alkylheterocycloalkyl” means an alkyl-heterocycloalkyl group in whichthe alkyl and heterocycloalkyl groups are as previously described. Thebond to the parent moiety is through the heterocycloalkyl group.

“Alkoxyalkyloxyalkyl” means an alkoxy-alkyl-O-alkyl group in which thealkoxy and alkyl groups are as previously described. The bond to theparent moiety is through the alkyl group.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Haloalkyl” means a halo-alkyl- group in which the alkyl group is aspreviously described. The bond to the parent moiety is through thealkyl. Non-limiting examples of suitable haloalkyl groups includefluoromethyl and difluoromethyl.

“Heteroarylalkenyl” means a heteroaryl-alkenyl group in which theheteroaryl and alkenyl are as previously described. Preferredheteroarylalkenyl contain a lower alkenyl group. The bond to the parentmoiety is through the alkenyl group.

“Heterocycloalkyloxy” means a heterocycloalkyl-O— group in which theheterocycloalkyl group is as previously described. The bond to theparent moiety is through the ether atom.

“Heteroarylalkoxyalkyl” means a heteroaryl-alkoxyalkyl group in whichthe heteroaryl and alkoxyalkyl groups are as described above. The bondto the parent moiety is through the alkyl group,

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Aminoalkyl” means an amino-alkyl group in which the alkyl group is aspreviously described. The bond to the parent moiety is through thealkyl.

“Alkenyloxy” means an alkenyl-O— group in which the alkenyl group is aspreviously described. The bond to the parent moiety is through the etheroxygen.

“Alkynyloxy” means an alkynyl-O— group in which the alkenyl group is aspreviously described. The bond to the parent moiety is through the etheroxygen.

“Aryloxyalkyl” means an aryl-O-alkyl group in which the aryl and alkylgroups are as previously described. Non-limiting examples of suitablearyloxyalkyl groups include phenoxymethyl and naphthoxymethyl. The bondto the parent moiety is through the alkyl group.

“Arylalkoxyalkyl” means an aryl-alkoxyalkyl group in which the aryl andalkoxyalkyl groups are as previously described. The bond to the parentmoiety is through the alkyl group.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

“Cycloalkenyloxy” means a cycloalkenyl-O— group in which thecycloalkenyl group is as previously described. The bond to the parentmoiety is through the ether atom.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

“Cycloalkyloxy” or “cycloalkoxy” means a cycloalkyl-O— group in whichthe cycloalkyl group is as previously described. The bond to the parentmoiety is through the ether atom.

“Cycloalkyloxyalkyl” means a cycloalkyl-O-alkyl group in which thecycloalkyl and alkyl groups are as previously described. The bond to theparent moiety is through the alkyl group.

“Haloalkoxyalkyl” means a halo alkoxyalkyl group in which thealkoxyalkyl group is as previously described. The bond to the parentmoiety is through the alkyl group.

“Heterocyclylalkoxyalkyl” means a heterocyclyl-alkoxyalkyl group inwhich the alkoxyalkyl group is as previously described. The bond to theparent moiety is through the alkyl group.

The optional double bond represented by

means that at least a single bond must be present, but that a doublebond can be present; when the double bond is present, R¹⁰ is absent.

When R⁴ and R⁵ join to form a ring with the nitrogen to which they areattached, the rings formed are 1-pyrrolidinyl, 1-piperidinyl and1-piperazinyl, wherein the piperazinyl ring may also be substituted atthe 4-position nitrogen by a group R⁷.

The above statements, wherein, for example, R⁴ and R⁵ are said to beindependently selected from a group of substituents, means that R⁴ andR⁵ are independently selected when attached to the same nitrogen, butalso that where an R⁴ or R⁵ variable occurs more than once in amolecule, those occurrences are independently selected. Similarly, eachoccurrence of R¹³ or R¹⁴ is independent of any other R¹³ or R¹⁴ in thesame Q ring. Those skilled in the art will recognize that the size andnature of the substituent(s) will affect the number of substituentswhich can be present.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

The structure

in the compound of formula I, represents an optional double bond, thedotted line is a bond or no bond, resulting in a double bond or a singlebond, as permitted by the valency requirement; with the proviso that R³is absent when the carbon to which R³ would be attached is part of adouble bond.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs, solvates, and co-crystals of the compounds of the inventionare also contemplated herein. A discussion of prodrugs is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, (1987) Edward B. Roche, ed., American Pharmaceutical Associationand Pergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂—C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,t-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₀-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₅)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sc., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

A co-crystal is a crystalline superstructure formed by combining anactive pharmaceutical intermediate with an inert molecule that producescrystallinity to the combined form. Co-crystals are often made between adicarboxlyic acid such as fumaric acid, succinic acid etc. and a basicamine such as the one represented by compound I of this invention indifferent proportions depending on the nature of the co-crystal.(Rmenar, J. F. et. al. J. Am. Chem. Soc. 2003, 125, 8456).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986)33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prod rugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be nor-secohimbacine derivatives useful as thrombin receptor antagonists.

Compounds of the invention have at least one asymmetrical carbon atomand therefore all isomers, including enantiomers, stereoisomers,rotamers, tautomers and racemates of the compounds of Formula (I) (wherethey exist) are contemplated as being part of this invention. Theinvention includes d and I isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound of Formula I.Isomers may also include geometric isomers, e.g., when a double bond ispresent. Polymorphous forms of the compounds of Formula (I), whethercrystalline or amorphous, also are contemplated as being part of thisinvention.

Typical preferred compounds of the present invention have the followingstereochemistry:

with compounds having that absolute stereochemistry being morepreferred.

Those skilled in the art will appreciate that for some compounds ofFormula I, one isomer will show greater pharmacological activity thanother isomers.

Compounds of the invention are prepared from tricyclic intermediates byprocedures known in the art; typical procedures are shown in Schemes 1and 2, below.

Following are examples of preparing starting materials and compounds offormula I. In the procedures, the following abbreviations are used:

rt room temperature

THF tetrahydrofuran

Et₂O ethyl ether

Me methyl

Et ethyl

EtOAc ethyl acetate

DCM Dichloromethane

DMF N,N-Dimethylformamide

DMAP Dimethylaminopyridine

LiHMDS or LHMDS:Lithium bis(trimethylsilyl)amide

Ti(OiPr)₄ titanium isopropoxide;

TLC thin layer chromatography

TMSI Trimethylsilyl iodide or iodotrimethylsilane

Lactones such as 4 and 5 can be prepared from the ketone 2 as describedin scheme 1. The ketone was alkylated with tert-butyl bromoacetate toprovide intermediate 3 which was reduced with sodium borohydride thencyclized to provide the cis and trans lactams 4 and 5.

Preparation of 2

To a solution of 1 (9.0 g, 23.3 mmol) (see U.S. Patent 2004/0152736 A1for the preparation of 1) in 150 ml THF at 0° C. was added LHMDS as a 1Msolution in THF (35 ml, 35 mmol, 1.5 eq.). The mixture was stirred for30 min. then evacuated and filled with oxygen using a balloon. Themixture was stirred under the oxygen atmosphere for 30 min at 0° C. and1 hr at rt. The reaction was quenched by the addition of aqueous sodiumsulfite, stirred for 1 hr and extracted with ethyl acetate. The crudeproduct obtained was purified by silica gel chromatography to obtain 300mg of 2 as a minor product.

MS: 331.1 (MH⁺)

Preparation of 3

To a solution of 2 (160 mg, 0.48 mmol) in 5 ml THF at 0° C. was added a1 M solution of LHMDS in THF (0.58 ml, 058 mmol, 1.2 eq) and afterstirring for 10 min, tert-buytl bromoacetate was added. The mixture wasstirred overnight while allowing warming to rt. It was quenched by theaddition of aqueous ammonium chloride, extracted with ethyl acetate andthe crude product was purified by preparative TLC using 30% ethylacetate in hexanes to provide 36 mg of 3.

Preparation of 4 and 5

To a solution of 3 (43 mg, 0.097 mmol) in 1 ml methanol at 0 PC wasadded NaBH₄ (4 mg, 0.106 mmol, 1.0 eq.) and stirred for 10 min. Thereaction was quenched by the addition of aqueous ammonium chloride andextracted with ethyl acetate to give 45 mg of crude product. This crudeproduct was stirred with 0.5 ml each of dichloromethane andtriftuoroacetic acid at rt for 2.5 hr. The solution was concentrated andthe crude product was purified by preparative TLC using 35% ethylacetate in hexanes to provide 16 mg of 4 and 21 mg of 5.

MS for 4: 373.1 (MH⁺)

MS for 5: 373.1 (MH⁺)

An alternate approach to the preparation of these types of compounds isdescribed in scheme 2. Carboxylic acid 6 was converted to the aldehyde 8via the alcohol 7. Horner-Wordsworth reaction with phosphonate 9 gavethe vinyl pyridine 10 which was α-hydroxylated to II. Reduction of thelactone to the lactol followed by reaction with Dess-Martin periodinanereagent gave formate 13 which under basic conditions gave the ketone 14.Alkylation with tert-butyl bromoacetate gave intermediates 15 and 16.Ketone 16 was reduced to the axial alcohol with L-selectride andcyclized to the lactone 17 under acidic conditions. Suzuki coupling of17 gave the target compounds 18-20.

Preparation of 7

To a solution of 6 (30 g, 0.119 mol) (see U.S. Pat. No. 6,063,847 forthe preparation of 6) in 400 ml dichloromethane was added oxalylchloride (21 ml, 0.241 mol. 2 eq.) followed by DMF (275 μl, 3.55 mmol, 5mot %). The mixture was stirred for 2 hr, concentrated and evaporatedwith toluene to provide the acid chloride. This was dissolved in 500 mlTHF, cooled to 0° C., added lithium tri-ter-butoxyaluminohydride (76 g,0.299 mol, 2.5 eq.) and the mixture was stirred for 2 hr. It was dilutedwith water, acidified with HCl, extracted with ethyl acetate to provide21.6 g of 7,

Preparation of 8

To a solution of 7 (12.0 g, 50.4 mmol) in 200 ml dichloromethane at 0°C. was added 2,2,6,6-tetramethylpiperidinooxy (160 mg, 1.02 mmol, 2 mol%) and a solution of potassium bromide (600 mg, 5.04 mmol, 0.1 eq.) in10 ml water. To this mixture was added drop by drop Clorox solution (929, ˜6.15% NaOCl content) saturated with solid NaHCO₃. After the additionwas complete, the mixture was stirred for 20 min, organic layerseparated and the aqueous layer extracted with dichloromethane. Thecombined organic layer washed with aq. Na₂S₂O₃, brine, dried over MgSO₄,filtered and concentrated to provide 12 g of 8 as a resin.

Preparation of 10

To a solution of 9 (20 g, 65 mmol) (see U.S. Patent Application No.2004/0152736 A1 for the preparation of 9) in 200 ml THF at 0° C. wasadded a 1 M solution of LHMDS in THF (65 ml, 65 mmol) and the mixturestirred for 30 min at 0° C. To this was added Ti(OPr)₄ (22.3 ml, 75.5mmol) followed by a solution of aldehyde 8 (12 g) in 50 ml THF. Themixture was stirred for 15 min at 0° C. and 30 min at rt then quenchedwith aq. NH₄Cl, Ethyl acetate extraction followed by chromatographicpurification using 0% to 15% ethyl acetate-hexanes gave 3.3 g of 10.

Preparation of 11

To a solution of 10 (3.3 g, 8.46 mmol) in 50 ml THF at 0° C. was added a1M solution of LHMDS in THF (12.7 ml, 12.7 mmol, 1.5 eq.) and stirredfor 30 min. The flask was evacuated and filled with oxygen and stirredunder the oxygen atmosphere for 1 hr at rt. It was quenched by theaddition of aq. Na₂SO₃, stirred for 30 min. extracted with ethyl acetateand purified by chromatography using 0% to 20% ethyl acetate-hexanes toprovide 3 g of 11.

MS: 406.1 (MH⁺)

Preparation of 12

To a solution of 11 (4.2 g, 10.3 mmol) in 75 ml dichloromethane at −78°C. was added a 20 wt % solution of DIBALH in toluene (34.2 mmol, 41.4mmol, 4 eq.) and stirred for 1 hr at −78° C. It was quenched by theaddition of aq. potassium sodium tartrate and extracted withdichloromethane to provide 2.89 g of 12.

MS; 408.22 (MH⁺)

Preparation of 13

To a solution of 12 (2.89 g, 7.08 mmol) in 50 ml dichloromethane at rtwas added NaHCO₃ (1.2 g, 14.28 mmol, 2 eq.) followed by Dess-Martinperiodinane (3.90 g, 9.19 mmol, 1.3 eq.) and the suspension was stirredfor 2 hr. The reaction mixture was diluted with ether and stirred withaq. Na₂S₂O₃ and NaHCO₃ until the two layers became clear. The organiclayer was separated and the aqueous layer was extracted with ether. Thecombined organic layer washed with aq. Na₂S₂O₃, NaHCO₃ mixture andbrine. The solution was dried over MgSO₄, filtered, concentrated andevaporated to provide ˜3.0 g of 13.

MS. 406.2 (MH⁺)

Preparation of 14

A solution of 14 (˜7.08 mmol) in 50 ml methanol was stirred with K₂CO₃(3.9 g, 28.2 mmol, 4 eq.) at rt for 3 hr and diluted with water. It wasextracted with ether and the crude product was chromatographed using 0%to 100% ethyl acetate—hexanes to provide 1.74 g of 14.

MS: 334.1 (MH⁺)

Preparation of 16

To a solution of 14 (1.39 g, 4.15 mmol) in 30 ml THF at 0° C. was addeda 1 M solution of LHMDS in THF (5.0 ml, 5.0 mmol, 1.2 eq.) and stirredfor 30 min then added tert-butyl bromoacetate (0.92 ml, 6.23 mmol, 1.5eq.) and the mixture stirred overnight allowing to warm to rt. Thesolution was diluted with aq. NH₄Cl, extracted with ethyl acetate andthe crude product was purified by chromatography to provide 920 mg of 15and 420 mg of 16 which contains about 20% of 14.

MS for 15: 448.1 (MH⁺)

MS for 16: 448.1 (MH⁺)

Preparation of 17

To a solution of 16 (420 mg, 0.937 mmol) in 10 ml THF at −78° C. wasadded 1 M solution of L-selectride in THF (2.8 ml, 2.8 mmol, 3 eq) andthe mixture stirred for 1 hr at −78° C. The reaction was quenched withthe addition of few drops of acetone and stirred for few minutes at rt.The solvent was concentrated to dryness and the residue was stirred with5 ml of dichloromethane and 10 ml of trifluoroacetic acid and stirred atrt for 2 hr. The solvent Was concentrated and taken in aq. NaHCO₃. Itwas extracted with ethyl acetate and purified by chromatography using 0%to 20% ethyl acetate—hexanes to provide 80 mg of 17.

MS: 376.2 (MH⁺)

Preparation of 18

A solution of 17 (25 mg, 0.066 mmol), m-fluorophenylboronic acid (19 mg,0.136 mmol, 2 eq.), K₂CO₃ (37 mg, 0.268 mmol, 4 eq.) and Pd(PPh₃)₄ (4mg, 3.5 μmol, 5 mol) in a mixture of 0.7 ml toluene, 0.3 ml ethanol and0.15 ml water was bubbled with argon and heated in a sealed tube at 100°C. for 5 hr. The solution was poured into water, extracted with ethylacetate, dried over MgSO₄, filtered, concentrated and purified bypreparative TLC using 10% ethyl acetate-dichloromethan to provide 6 mgof 18.

Compounds 19 and 20 were prepared using analogous procedures.

MS for 18: 392.1 (MH⁺)

MS for 19: 442.1 (MH⁺)

MS for 20: 399.1 (MH⁺)

Further embodiments of the invention encompass the administration ofcompounds of Formula I along with at least one additional agent. Thecontemplated additional agent is one that differs in either atomic makeup or arrangement from the compounds of Formula I. Additional agentsthat can be used in combination with the novel compounds of thisinvention include drugs that are useful in treating thrombosis-relateddiseases including thrombosis, atherosclerosis, restenosis,hypertension, angina pectoris, angiogenesis related disorders,arrhythmia, a cardiovascular or circulatory disease or condition, heartfailure, myocardial infarction, glomerulonephritis, thrombotic stroke,thromboembolytic stroke, peripheral vascular diseases, cerebralischemia, rheumatoid arthritis, rheumatism, astrogliosis, a fibroticdisorder of the liver, kidney, lung or intestinal tract, systemic lupuserythematosus, multiple sclerosis, osteoporosis, glomerulonephritis,renal disease, acute renal failure, chronic renal failure, renalvascular homeostasis, renal ischemia, bladder inflammation, diabetes,diabetic neuropathy, cerebral stroke, cerebral ischemia, nephritis,cancer, melanoma, renal cell carcinoma, neuropathy and/or malignanttumors, neurodegenerative and/or neurotoxic diseases, conditions, orinjuries, inflammation, asthma, glaucoma, macular degeneration,psoriasis, endothelial dysfunction disorders of the liver, kidney orlung inflammatory disorders of the lungs and gastrointestinal tract,respiratory tract disease or condition, radiation fibrosis, endothelialdysfunction, periodontal diseases or wounds or a spinal cord injury, ora symptom or result thereof, as well as other disorders in whichthrombin and its receptor play a pathological role.

Suitable cardiovascular agents are selected from the group consisting ofthromboxane A2 biosynthesis inhibitors; thromboxane antagonists;adenosine diphosphate inhibitors; cyclooxygenase inhibitors; angiotensinantagonists; endothelin antagonists; phosphodiesterase inhibitors;angiotensin converting enzyme inhibitors; neutral endopeptidaseinhibitors; anticoagulants; diuretics; platelet aggregation inhibitors;and GP IIb/IIIa antagonists.

Preferred types of drugs for use in combination with the novel compoundsof this invention are thromboxane A2 biosynthesis inhibitors, GPIIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphateinhibitors, cyclooxygenase inhibitors, angiotensin antagonists,endothelin antagonists, angiotensin converting enzyme inhibitors,neutral endopeptidase inhibitors, anticoagulants, diuretics, andplatelet aggregation inhibitors.

In particular, suitable cardiovascular agents are selected from thegroup consisting of aspirin, seratrodast, picotamide and ramatroban,clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan,candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone,enoximone, captopril, enalapril, enatiprilat, spirapril, quinapril,perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril,benazapril, candoxatril, ecadotril, ximelagatran, fondaparin,enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid,furosemide, amiloride, abciximab, eptifibatide, parsugrel and fragmin.

Especially preferred for use in the combinations are aspirin, cangrelor,clopidogrel bisulfate, parsugrel and fragmin.

When the invention comprises a combination of a compound of Formula Iand another agent, the two active components may be co-administeredsimultaneously or sequentially, or a single pharmaceutical compositioncomprising a compound of Formula I and another agent in apharmaceutically acceptable carrier can be administered. The componentsof the combination can be administered individually or together in anyconventional dosage form such as capsule, tablet, powder, cachet,suspension, solution, suppository, nasal spray, etc. The dosage of theadditional agent can be determined from published material, and mayrange from 1 to 1000 mg per dose.

In this specification, the term “at least one compound of Formula I”means that one to three different compounds of Formula I may be used ina pharmaceutical composition or method of treatment. Preferably onecompound of Formula I is used. Similarly, the term “one or moreadditional cardiovascular agents” means that one to three additionaldrugs may be administered in combination with a compound of Formula I;preferably, one additional compound is administered in combination witha compound of Formula I. The additional agents can be administeredsequentially or simultaneously with reference to the compound of FormulaI.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A, Gennaro (ed.), The Science and Practice of Pharmacy,20^(th) Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 150 mg, preferably fromabout 1 mg to about 75 mg, more preferably from about 1 mg to about 50mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two tofour divided doses.

When separate compounds of Formula I and the other agents are to beadministered as separate compositions, they can be provided in a kitcomprising in a single package, one container comprising a compound ofFormula I in a pharmaceutically acceptable carrier, and a separatecontainer comprising another cardiovascular agent in a pharmaceuticallyacceptable carrier, with the compound of Formula I and the other agentbeing present in amounts such that the combination is therapeuticallyeffective. A kit is advantageous for administering a combination when,for example, the components must be administered at different timeintervals or when they are in different dosage forms.

The activity of the compounds of formula I can be determined by thefollowing procedures.

In Vitro Testing Procedure for Thrombin Receptor Antagonists Preparationof [³H]haTRAP

A(pF-F)R(ChA)(hR)(I₂—Y)—NH₂ (1.03 mg) and 10% Pd/C (5.07 mg) weresuspended in DMF (250 μl) and diisopropylethylamine (10 μl). The vesselwas attached to the tritium line, frozen in liquid nitrogen andevacuated. Tritium gas (342 mCi) was then added to the flask, which wasstirred at room temperature for 2 hours. At the completion of thereaction, the excess tritium was removed and the reacted peptidesolution was diluted with DMF (0.5 ml) and filtered to remove thecatalyst. The collected DMF solution of the crude peptide was dilutedwith water and freeze dried to remove the labile tritium. The solidpeptide was redissolved in water and the freeze drying process repeated.The tritiated peptide ([³H]haTRAP) was dissolved in 0.5 ml of 0.1%aqueous TFA and purified by HPLC using the following conditions: column,Vydac™ C18, 25 cm×9.4 mm I.D.; mobile phase, (A) 0.1% TFA in water, (B)0.1% TFA in CH₃CN; gradient, (A/B) from 100/0 to 40/60 over 30 min; flowrate, 5 ml/min; detection, UV at 215 nm. The radiochemical purity of[³H]haTRAP was 99% as analyzed by HPLC. A batch of 14.9 mCi at aspecific activity of 18.4 Ci/mmol was obtained.

Preparation of Platelet Membranes

Platelet membranes were prepared using a modification of the method ofNatarajan et al. (Natarajan et al, Int. J. Peptide Protein Res.45:145-151 (1995)) from 20 units of platelet concentrates obtained fromthe North Jersey Blood Center (East Orange, N.J.) within 48 hours ofcollection. All steps were carried out at 4° C. under approved biohazardsafety conditions. Platelets were centrifuged at 100×g for 20 minutes at4° C. to remove red cells. The supernatants were decanted andcentrifuged at 3000×g for 15 minutes to pellet platelets. Platelets werere-suspended in 10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM EDTA, to atotal volume of 200 ml and centrifuged at 4400×g for 10 minutes. Thisstep was repeated two additional times. Platelets were re-suspended in 5mM Tris-HCl, pH 7.5, 5 mM EDITA to a final volume of approximately 30 mland were homogenized with 20 strokes in a Dounce™ homogenizer. Membraneswere pelleted at 41,000×g, re-suspended in 40-50 ml 20 mM Tris-HCl, pH7.5, 1 mM EDTA, 0.1 mM dithiothreitol, and 10 ml aliquots were frozen inliquid N₂ and stored at −80° C. To complete membrane preparation,aliquots were thawed, pooled, and homogenized with 5 strokes of a Douncehomogenizer. Membranes were pelleted and washed 3 times in 10 mMtriethanolamine-HCl, pH 7.4, 5 mM EDTA, and re-suspended in 20-25 ml 50mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM EGTA, and 1% DMSO. Aliquots ofmembranes were frozen in liquid N₂ and stored at −80° C. Membranes werestable for at least 3 months. 20 units of platelet concentratestypically yielded 250 mg of membrane protein. Protein concentration wasdetermined by a Lowry assay (Lowry et al., J. Biol. Chem., 193:265-275(1951)).

High Throughput Thrombin Receptor Radioligand Binding Assay

Thrombin receptor antagonists were screened using a modification of thethrombin receptor radioligand binding assay of Ahn et al. (Ahn et al.,Mol. Pharmacol, 51:350-356 (1997)). The assay was performed in 96 wellNunc plates (Cat. No. 269620) at a final assay volume of 200 μl.Platelet membranes and [³H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM,respectively, in binding buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1mM EGTA, 0.1% BSA). Stock solutions (10 mM in 100% DMSO) of testcompounds were further diluted in 100% DMSO. Unless otherwise indicated,10 μl of diluted compound solutions and 90 μl of radioligand (a finalconcentration of 10 nM in 5% DMSO) were added to each well, and thereaction was started by the addition of 100 μl of membranes (40 μgprotein/well). The binding was not significantly inhibited by 5% DMSO.Compounds were tested at three concentrations (0.1, 1 and 10 μM). Theplates were covered and vortex-mixed gently on a Lab-Line™ Titer PlateShaker for 1 hour at room temperature. Packard UniFilter™ GF/C filterplates were soaked for at least 1 hour in 0.1% polyethyleneimine. Theincubated membranes were harvested using a Packard FilterMate™ UniversalHarvester and were rapidly washed four times with 300 μl ice cold 50 mMTris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM EGTA. MicroScint™ 20 scintillationcocktail (25 μl) was added to each well, and the plates were counted ina Packard TopCount™ Microplate Scintillation Counter. The specificbinding was defined as the total binding minus the nonspecific bindingobserved in the presence of excess (50 μM) unlabeled haTRAP. The %inhibition by a compound of [³H]haTRAP binding to thrombin receptors wascalculated from the following relationship:

% Inhibition=Total binding-Binding in the presence of a testcompound×100 Total binding-Nonspecific binding Materials

A(pF-F)R(ChA)(hR)Y—NH₂ and A(pF-F)R(ChA)(hR)(I₂—Y)—NH₂, were customsynthesized by AnaSpec Inc. (San Jose, Calif.). The purity of thesepeptides was >95%. Tritium gas (97%) was purchased from EG&G Mound,Miamisburg, Ohio. The gas was subsequently loaded and stored on an IN/USSystems Inc. Trisorber. MicroScint™ 20 scintillation cocktail wasobtained from Packard Instrument Co.

Cannabinoid CB₂ Receptor Binding Assay

Binding to the human cannabinoid CB₂ receptor was carried out using theprocedure of Showalter, et al. (1996, J. Pharmacol Exp Ther. 278(3),989-99), with minor modifications. All assays were carried out in afinal volume of 100 ul. Test compounds were re-suspended to 10 mM inDMSO, then serially diluted in 50 mM Tris, pH 7.1, 3 mM MgCl₂, 1 mMEDTA, 50% DMSO. Aliquots (10 ul) of each diluted sample were thentransferred into individual wells of a 96-well microtiter plate.Membranes from human CB₂ transfected CHO/Ki cells (Receptor Biology,Inc) were re-suspended in binding buffer (50 mM Tris, pH 7.1, 3 mMMgCl₂, 1 mM EDTA, 0.1% fatty acid free bovine serum albumin), then addedto the binding reaction (˜15 ug in 50 ul per assay). The reactions wereinitiated with the addition of [³H] CP-55, 940 diluted in binding buffer(specific activity=180 Ci/mmol; New England Nuclear, Boston, Mass.). Thefinal ligand concentration in the binding reaction was 0.48 nM.Following incubation at room temperature for 2 hours, membranes wereharvested by filtration through pretreated (0.5% polyethylenimine; SigmaP-3143) GF-C filter plates (Unifilter-96, Packard) using a TomTec™ Mach3U 96-well cell harvester (Hamden, Conn.). Plates were washed 10 timesin 100 ul binding buffer, and the membranes allowed to air dry.Radioactivity on membranes was quantitated following addition of PackardOmniscint™ 20 scintillation fluid using a TopCount™ NXT Microplate

Scintillation and Luminescence Counter (Packard, Meriden, Conn.).Non-linear regression analysis was performed using Prism™ 20b. (GraphPadSoftware, San Diego, Calif.).

Using the test procedures described above, representative compounds offormula I were found to have thrombin receptor K₁ values ranging fromabout 3 nM to about 20 nM and thrombin receptor IC₅₀ values ranging fromabout 5 nM to about 70 nM as shown in Table 1 below.

TABLE I Compound No. Structure K_(i) IC₅₀ 1

45 nM 2

11 nM 16 nM 3

3.1 nM  4.8 nM  4

13 nM 20 nM 5

4.3 nM  6.7 nM 

1. A compound of Formula IK or Formula IIK

or a pharmaceutically acceptable salt thereof wherein:

Het is a pyridyl group wherein the pyridyl group is attached to B by acarbon atom ring member, and wherein the pyridyl group is substituted by1 to 4 moieties, W, wherein each W is independently selected from thegroup consisting of: hydrogen, alkyl, aryl or aryl substituted by 1 to 3substituents independently selected from the group consisting of alkyl,halogen, alkoxy, —CN, —CF₃, —OCF₃ or —OH; R¹ is hydrogen, alkyl,fluroalkyl, difluroralkyl or trifluroralkyl; R² is hydrogen, alkyl,fluroalkyl, difluroralkyl or trifluroralkyl; R⁹ is hydrogen; R¹⁰ and R¹¹are H or alkyl;

R³² and R³³ are H or alkyl.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein R³² and R³³, which canbe the same or different, are each alkyl.
 3. The compound of claim 1 ora pharmaceutically acceptable salt thereof, wherein R³² and R³³ are eachmethyl.
 4. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein Q is


5. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein W is phenyl, which is unsubstituted or substituted by agroup selected from the group consisting of halogen or —CN.
 6. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R⁹, R¹⁰ and R¹¹ are hydrogen.
 7. A compound of the formula or apharmaceutically acceptable salt thereof, which is:


8. A pharmaceutical composition comprising an effective amount of atleast one compound of claim 1 and a pharmaceutically acceptable carrier.9. A compound of claim 1 or a pharmaceutically acceptable salt thereofin purified form.
 10. A compound of claim 1 or a pharmaceuticallyacceptable salt thereof in isolated form.